Electroconvulsive therapy (ECT) is a highly effective treatment for major depressive disorder (MDD) that is helpful for patients with the most severe forms of affective illness. Relapse after successful acute phase ECT or pharmacotherapy practice is to prescribe an antidepressant (e.g., a tricyclic, a selective serotonin reuptake inhibitor (SSRI) or lithium) as continuation therapy. Recent studies show an alarmingly high relapse rate after ECT despite conventional continuation pharmacotherapy (C-PHARM). Continuation ECT (C-ECT) is also in widespread clinical use, however, its efficacy and safety have never been rigorously tested. The role of C-ECT in relapse prevention of seriously ill patients with MDD urgently needs to be defined. Currently, there is no information on the relative efficacy and safety of C-ECT in comparison to the traditional approach of C-PHARM. In a prospective, six-month, randomized single blind trial, we will compare the relative efficacy of an aggressive pharmacological strategy [nortriptyline and lithium in combination, and C-ECT in the prevention of relapse in patients with MDD who have responded to ECT. The major hypothesis is that C-ECT will more effectively prevent relapse than C-PHARM. Investigators at 4 sites will randomize 228 patients over 4 years. Raters at each site will evaluate symptoms and side effects. On the basis of edited videotapes obtained at regular intervals, a site-independent, blinded evaluator also will assess symptoms. A neuropsychological battery will be administered prior to acute phase ECT, shortly after the ECT course, 3-months after the end of acute phase treatment, and at the end of the 6-month continuation trial. These continuation therapies will be compared in their effects on relapse, cognitive performance, global functioning, side effects, and perceived health status. NOR and LI levels will be optimized by blood level monitoring. Bilateral ECT, at progressively increasing intervals, will be used for C-ECT. Methods are included to ensure the integrity of clinical diagnoses, symptom severity assessment, data collection and entry, and treatment delivery. In all patients, surreptitious use of prescription or recreational drugs will be monitored by urine testing.